Chronic lung diseases such as asthma and chronic obstructive pulmonary disease are associated with continual injury and repair. Epithelial regeneration after injury is a key component in restoring lung function, and requires the coordinate regulation of progenitor cell proliferation, survival and differentiation. Type II cells serve as epithelial progenitor cells and play a crucial role in epithelial repair after injury. The long-term objective of the present work is to elucidate the molecular mechanisms governing epithelial remodeling in chronic lung disease with the goal of developing novel approaches to disease diagnosis, treatment and prevention. The central hypothesis is that Rb and pl6 act as distinct and critical regulators of type II cell proliferation and survival. Preliminary data demonstrate age and Rb dependent pl6 induction in lung epithelial progenitor cells in vivo, and provide evidence that Rb and pl6 regulate type II cell growth. Aim one in this proposal is designed to determine critical Rb and pl6 functions essential in regulating type II progenitor cell growth in culture. Cellular proliferation and survival will be assessed in Rb, pl6 and Rb/pl6 deficient primary type II cultures obtained from murine lungs wherein Rb ablation is targeted to the lung epithelium in apl6 proficient or null background. Results will be compared to wild type controls to determine unique and overlapping Rb and pl6 functions. The second aim will elucidate the physiologic role of pl6 induction on lung epithelial cell growth in vivo. Effects of combined Rb and pl6 loss on lung morphogenesis, cell proliferation and cell survival will be assessed and compared to wild type as well as Rb or pl6 deficient lungs. These studies will directly determine the physiologic relevance of pl6 induction in vivo and elucidate molecular mechanisms underlying pl6 function in pulmonary progenitor cells in vivo. Completion of this work will result in novel insights into regulatory pathways governing lung epithelial regeneration by identifying key molecular mediators of pulmonary epithelial cell growth and survival. Public Health Relevance: More than 35 million Americans suffer from chronic lung diseases that cause significant morbidity and mortality. The Rb/pl6 pathway plays a fundamental role in regulating cell growth, differentiation and survival. This proposal aims to elucidate Rb and pl6 dependent mechanisms controlling lung epithelial progenitor cell growth. These studies are expected to improve understanding of the molecular and physiological basis of disease thereby facilitating development of novel approaches to treatment.